1. Field of the Invention
The present invention generally relates to paclitaxel derivatives and, more particularly, paclitaxel derivatives that are conformationally constrained.
2. Background Description
Paclitaxel (PTX or “Taxol™”) is a natural product and is the world's leading anticancer drug. With reference to FIG. 1, PTX (1a) and its closely related, semi-synthetic, analog docetaxel (1b) are clinically approved drugs for several tumor malignancies. These molecules, including several other newly discovered natural products (e.g., epothilones, discodermolide and eleutherobin), induce apoptotic cell death by promoting polymerization of tubulin to microtubules and their stabilization. Significant advances have been made since the discovery and publication of the electronic crystallographic 3.7 Angstrom zinc induced tubulin structure (see, Nogales, et al., Nature, 391:199-203 (1998). This model, however, lacks the resolution to define the paclitaxel three-dimensional interaction on tubulin polymer.
Paclitaxel is a complex molecule and is expensive to produce in large quantities. A clear understanding of the three dimensional interaction of PTX in the binding site on the tubulin receptor would be beneficial for the rational design of new generation drugs. There has been ample evidence available from 2D NMR analysis and modeling studies to support the three bioactive models proposed for PTX. The polar (extended) conformation with clustering of C-2 benzoate and C-3′-benzamide side chain was proposed as a bioactive conformer. Similarly, several reports appeared in favor of a hydrophobic collapse conformation clustering of C-2 benzoate and the C-3′ phenyl group. The hydrophobic collapse conformation was also proposed by the inventors of the present invention based upon the combination of fluorescent spectroscopy using FRET measurements and REDOR NMR studies. However, none of the conformationally constrained analogs synthesized to date, based on any of the above models, resulted in equal or more active PTX analogs than the parent compound itself. In most cases they were inactive, and in some cases they exhibited 2-30 fold less bioactivity, with respect to PTX.
Given the significant advantages of PTX and related compounds in patient care for a wide range of disorders (human cancers including breast, ovarian, and lung cancer; neurodegenerative disorders such as Alzheimer's disease, etc.), it would be beneficial to have alternative derivatives that are as active or more active, or that are easier to mass produce.